Background-Asymmetric dimethylarginine (ADMA) is an endogenous competitive inhibitor of nitric oxide (NO) synthase. Because endothelial NO elaboration is impaired in hypercholesterolemia, we investigated whether plasma concentrations of ADMA are elevated in young, clinically asymptomatic hypercholesterolemic adults. We further studied whether such elevation of ADMA levels was correlated with impaired endothelium-dependent, NO-mediated vasodilation and urinary nitrate excretion. In a randomized, double-blind, placebo-controlled study, we investigated whether these changes could be reversed with exogenous L-arginine. Methods and Results-We measured plasma levels of L-arginine, ADMA, and symmetrical dimethylarginine (SDMA) by high-performance liquid chromatography in 49 hypercholesterolemic (HC) and 31 normocholesterolemic (NC) humans. In 8 HC subjects, endothelium-dependent forearm vasodilation was assessed before and after an intravenous infusion of L-arginine or placebo and compared with 8 NC control subjects. ADMA levels were significantly elevated by Ͼ100%

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Asymmetrical dimethylarginine (ADMA) is an endogenous nitric oxide synthase inhibitor. It is formed by protein arginine N-methyltransferases (PRMTs), which utilize S-adenosylmethionine as methyl group donor. ADMA plasma concentration is elevated in hypercholesterolemia, leading to endothelial dysfunction and producing proatherogenic changes of endothelial cell function. Four different isoforms of human PRMTs have been identified. Because the release of ADMA from human endothelial cells is increased in the presence of native or oxidized LDL cholesterol, we investigated the potential involvement of PRMT activity and gene expression in this effect. We found that the production of ADMA by human endothelial cells is upregulated in the presence of methionine or homocysteine and inhibited by either of the methyltransferase inhibitors S-adenosylhomocysteine, adenosine dialdehyde, or cycloleucine. This effect is specific for ADMA but not symmetrical dimethylarginine. The upregulation of ADMA release by native and oxidized LDL is abolished by S-adenosylhomocysteine and by the antioxidant pyrrollidine dithiocarbamate. Furthermore, a methyl-(14)C label is transferred from S-adenosylmethionine to ADMA but not symmetrical dimethylarginine, in human endothelial cells. The expression of PRMTs is upregulated in the presence of native or oxidized LDL. Our data suggest that the production of ADMA by human endothelial cells is regulated by S-adenosylmethionine-dependent methyltransferases. This activity is upregulated by LDL cholesterol, which may be due in part to the enhanced gene expression of PRMTs. In concentrations reached by stimulation of methyltransferases (5 to 50 micromol/L), ADMA significantly inhibited the formation of (15)N-nitrite from L-[guanidino-(15)N(2)]arginine. These findings suggest a novel mechanism by which ADMA concentration is elevated in hypercholesterolemia, leading to endothelial dysfunction and atherosclerosis.

In PAOD patients, there is a progressive reduction in urinary nitrate and cGMP excretion rates, which may be caused in part by accumulation of ADMA, an endogenous inhibitor of NO synthase.

Background— Increased blood concentrations of the endogenous nitric oxide synthase (NOS) inhibitor asymmetrical dimethylarginine (ADMA) have been linked to excess cardiovascular morbidity and mortality and to progression of renal disease. We evaluated systemic cardiovascular effects of ADMA infusion in healthy subjects using invasive techniques, ie, right heart catheter and inulin/para-aminohippurate clearance. Methods and Results— Plasma ADMA concentrations encountered in patients with cardiovascular diseases, ie, between 2 and 10 μmol/L, caused a significant ( P <0.05) decrease in concentrations of plasma cGMP, the main second messenger of NO. In addition, cardiac output was significantly lower (5.3±0.4 versus 5.8±0.6 L/min; P <0.05 versus baseline), and systemic vascular resistance was significantly higher (1403±123 versus 1221±100 dyn · s · cm −5 ; P <0.05 versus baseline). The infusion of 0.25 mg ADMA · kg −1 · min −1 or 3 μg N G -nitro- l -arginine methyl ester · kg −1 · min −1 , a potent synthetic NOS inhibitor with long action, resulted in a comparable decrease in effective renal plasma flow (from 670±40 to 596±29 mL · min −1 ; P <0.05) and an increase in renovascular resistance (from 79±5 to 90±7 mm Hg · mL −1 · min −1 ; P <0.05). Moreover, administration of ADMA caused significant sodium retention and blood pressure increase (both P <0.05). The observed effects of ADMA in the systemic circulation were sustained corresponding to a mean plasma half-life of 23.5±6.8 minutes, calculated from plasma ADMA decay curves in healthy subjects. Conclusions— Systemic ADMA infusion is responsible for a short-term, modest decrease in cardiac output with comparable decrease in effective renal plasma flow while increasing systemic vascular resistance and blood pressure in a dose-related manner.

Reduced bioavailability of nitric oxide (NO) is thought to play an important role in progression of renal damage. The hypothesis that the endogenous NO synthase inhibitor asymmetric dimethylarginine (ADMA) is involved in progression of kidney disease was tested. Plasma ADMA concentrations and other putative progression factors were assessed in 227 relatively young patients (45.7 ؎ 12.6 yr) with nondiabetic kidney diseases and mild to moderate renal failure. Progression assessed as doubling of serum creatinine and/or renal replacement therapy was evaluated prospectively. Baseline plasma ADMA concentrations in renal patients correlated significantly with serum creatinine (r ‫؍‬ 0.595), GFR (r ‫؍‬ ؊0.591), age (r ‫؍‬ 0.281), and proteinuria (r ‫؍‬ 0.184; all P < 0.01). Patients who reached an end point during follow-up were significantly older (P < 0.05) and had significantly higher creatinine, ADMA, and parathyroid hormone blood concentrations and protein excretion rates at baseline, whereas GFR and hemoglobin were significantly lower (all P < 0.01). Cox regression analysis revealed baseline serum creatinine (odds ratio 2.00; 95% confidence interval [CI] 1.61 to 2.49; P < 0.001) and ADMA (odds ratio 1.47; 95% CI 1.12 to 1.93 for an increment of 0.1 mol/L; P < 0.006) as independent predictors of disease progression. In patients with ADMA levels above median, progression was significantly faster (P < 0.0001), and their mean follow-up time to a progression end point was 52.8 mo (95% CI 46.9 to 58.8) as compared with 71.6 mo (95% CI 66.2 to 76.9) in patients with ADMA levels below the median. The endogenous NO synthase inhibitor ADMA is significantly associated with progression of nondiabetic kidney diseases. Lowering plasma ADMA concentrations may be a novel therapeutic target to prevent progressive renal impairment.

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Symmetrical dimethylarginine (SDMA) is the structural isomer of the endogenous nitric oxide synthase (NOS) inhibitor asymmetric dimethylarginine. Whereas the major route of asymmetric dimethylarginine elimination is the hydrolytic degradation by dimethylarginine dimethylaminohydrolase, SDMA is eliminated by renal excretion. SDMA does not directly inhibit NOS but is a competitor of arginine transport. This study showed for the first time that measurement of SDMA can be a marker of estimated GFR and extent of coronary artery disease (CAD). In 97 patients with CAD, SDMA was a marker of estimated GFR. On multiple regression analysis of the CAD parameter stenosis score, SDMA was the only parameter retained. In addition, endothelial cells from the third passage were cultured in medium that contained 70 mol/L arginine and was incubated for 24 h in the presence of various concentration of SDMA (0, 2, 5, 10, and 100 mol/L). The levels of nitrate and nitrite in conditioned media, the protein expression of NOS, and the content of reactive oxygen species in endothelial cells were determined. SDMA inhibited dose dependently the NO synthesis in intact endothelial cells, whereas it had no effect on protein expression of NOS. This effect was associated with an increase in reactive oxygen species. Co-incubation with S ymmetrical dimethylarginine (SDMA) is the structural isomer of the endogenous nitric oxide synthase (NOS) inhibitor asymmetric dimethylarginine (ADMA). ADMA has been shown to correlate with risk factors for coronary artery disease (CAD) such as hypertension (1,2), hypercholesterolemia (3), hyperhomocysteinemia (4 -6), insulin resistance (7), age (1), and mean arterial pressure (1). Moreover, ADMA correlates with the extent and the severity of coronary atherosclerosis (8) and is a strong and independent marker of cardiovascular events and mortality in selected patient populations (9 -11). Although there is mounting evidence that chronically elevated ADMA may contribute to progression of vascular disease via endothelial damage, little attention has been paid to the role of SDMA. Both ADMA and SDMA derive from intranuclear methylation of l-arginine residuals and are released into the cytoplasm after proteolysis (12). SDMA is produced by protein-arginine methyltransferase 5 (PRMT 5) and PRMT 7 (both type II methyltransferases) (13,14). Only ADMA but not SDMA is metabolized by dimethylarginine dimethylaminohydrolase to citrulline and dimethylamine (15). SDMA seems to be strictly eliminated by renal excretion (16,17). A recent study by Fliser et al. (18) showed a very close correlation among serum creatinine, GFR (measured by iodothalamate clearance technique), and SDMA. The authors speculated that SDMA, equal to serum creatinine, can serve as a marker of renal function, but SDMA seems to be more than a simple indicator of renal function. In animals, a high-fat, high-cholesterol diet increases SDMA serum levels (19,20) without affecting renal function (20), indicating that cardiovascular risk factors other than impaired...